Project Summary/Abstract This is a resubmission of an application that aims to investigate how maternal inflammation during pregnancy influences clinical, neurocognitive, and neural characteristics in adult offspring during the late middle-age period. Accumulating evidence suggests that maternal inflammation and infection during pregnancy increase risk for schizophrenia and depression in offspring, as well as for more severe outcomes among schizophrenia cases. However, no studies have determined whether difficulties persist into later periods of development, and the ability to draw inferences from existing studies has been limited by a variety of factors, such as selecting participants based on mental disorder status of offspring. Due to these limitations, previous studies have been unable to control variability in the level of exposure to inflammation within groups, control for potential confounding factors, and include outcomes that may be more directly linked to inflammation than psychiatric diagnoses. The proposed project aims to randomly select participants from a birth cohort with previously analyzed cytokine data to determine whether variability in fetal exposure to inflammation is related to specific neural and symptomatic outcomes that occur across disorders, which could provide findings pertinent to a range of neurodevelopmental sequelae. The proposed study is based on a very unique cohort, the Child Health and Development Study (CHDS), with biosamples collected during pregnancy, continual follow-up of offspring through adolescence, and assessment of a multitude of potential pre- and postnatal covariates. Specifically, 20,000 women were followed throughout their pregnancies from 1959-1966; a subset of offspring were given a range of assessments at multiple points from birth to adolescence. Previous findings from our group indicated consistent links between 2nd trimester inflammation and infection to increased risk of offspring depression, as well as childhood difficulties (e.g., internalization). The proposed project will collect detailed clinical (questionnaires, semi-structured interviews, and laboratory tasks), neurocognitive, and brain (multi- modal MRI) indices for offspring exposed to varying levels of inflammation in utero. The specific aims are as follows: to investigate whether fetal exposure to higher levels of inflammation increases risk for 1) specific symptom dimensions among offspring (e.g., psychotic symptoms, reward functioning, depression), and/or for 2) specific neurocognitive and neurological outcomes among offspring (assessed using multi-modal brain imaging and neuropsychological testing), and 3) to determine whether links between fetal exposure to inflammation and childhood/adolescent outcomes persist into middle-age. The proposed study is uniquely positioned to answer key questions about how maternal inflammation during pregnancy contributes to neurocognitive, brain, and clinical disturbances in offspring at various periods of development, has the potential to influence the development of intervention and prevention strategies, and could help clarify the role of inflammation in neurodevelopment and in a variety of mental disorders.